The present invention is generally directed to a miniature light source for administering photodynamic therapy (PDT), a system incorporating same, and a method for providing such treatment, and more specifically, pertains to an minimal invasively implantable miniature light source which is operably coupled to a power supply that is either acoustically energized or acoustically activated to operate, and to a method for using such a miniature light source to administer PDT.
A tumor comprising abnormal cells is known to selectively absorb certain dyes perfused into the site to a much greater extent than surrounding tissue. For example, compared to normal cells, intracranial gliomas absorb up to a 28 times as much dye. Once pre-sensitized by dye tagging in this manner, the cancerous or abnormal cells can be destroyed by irradiation with light of an appropriate wavelength, several discrete wavelengths or waveband corresponding to an absorbing wavelength, several discrete wavelengths or waveband of the dye, with minimal damage to normal tissue. This procedure, which is known as photodynamic therapy (PDT), has been clinically used to treat metastatic breast cancer, bladder cancer, lung carcinomas, esophageal cancer, basal cell carcinoma, malignant melanoma, ocular tumors, head and neck cancers, and other types of malignant tumors, and for destroying pathogens. Because PDT may be selective in destroying abnormal cells that have absorbed more of the dye, it can successfully be used to kill malignant tissue or organisms with less effect on surrounding benign tissue in the brain and other critical areas.
Typically, invasive applications of PDT have been used during surgical procedures employed to gain access to a treatment site inside the body of the patient. Relatively high intensity light sources have traditionally been used to reduce the duration of the treatment, and thus the time required for the surgery used to expose the treatment site, and because the majority of the prior art teaches that very high intensity light will more likely kill all of the malignant cells. Optical fibers in a hand-held probe are often used to deliver the intense light to the surgically exposed treatment site from a remote light source to reduce damage to surrounding tissue from the heat developed by the light source. High power lasers or solid-state laser diode (LD) arrays in a remote light source coupled to the optical fibers are normally used. A typical prior art light source for PDT would provide from about 0.10 watts to more than 1.0 watts of optical power to achieve the high intensity, short duration exposures that are preferred. Because of the relatively high light intensity and power required to achieve it, apparatus to provide PDT is often physically too large and too heavy to be readily moved about with the patient.
The theoretical basis behind PDT is that the light energy absorbed by dye molecules in the malignant or pathogen cells is transferred to dissolved oxygen to produce a reactive species called xe2x80x9csinglet oxygen.xe2x80x9d This highly reactive form of oxygen kills cancer cells, damages tumor vasculature, and can destroy viruses and bacteria. Since the concentration of dissolved oxygen in cells is comparatively low, it is possible that after all available oxygen is activated and/or reacted with the cell materials, any additional increase in light intensity will have a negligible incremental effect on the tumor or in killing malignant cells. The limiting factor on the rate of malignant cell death in PDT may well be the rate at which additional oxygen diffuses into the treatment site from surrounding tissue and through replenishment via the vascular system. Contrary to the teachings of most of the prior art, the effectiveness of each photon of light impacting the treatment area may be highest at very low light intensities, provided over extended treatment times, and the optical efficiency may in fact decrease with increasing exposure level.
Several researchers, including Haas et al, xe2x80x9cPhotodynamic Effects of Dyes on Bacteriaxe2x80x9d Published in Mutation Researchh, 1979, vol. 60, pp. 1-11, have shown that the level of cytotoxicity in PDT appears to be proportional to the product of the integrated light exposure and the photoreactive agent""s concentration, rather than to the instantaneous light intensity. In other words, the degree of PDT response is dominated by the total amount of light absorbed by the photoreactive agent over the treatment period. It can therefore be argued that if: (i) the photoreactive agent""s concentration in the target tissue is maintained at a therapeutic level; and (ii) apparatus for delivering light of the proper wavelength, several discrete wavelengths or waveband to a treatment site over an extended period is available, then the benefits of PDT can be realized with a less aggressive and potentially less costly treatment carried out over a period ranging from days to weeks. Longer treatment periods at lower dosage rates may have other benefits as well, since high dosage rates continued over extended periods can result in adverse normal tissue response.
Maintenance of therapeutic photoreactive agent levels at a treatment site in the body is not difficult. It is well known that many PDT photoreactive agents have a long half-life in the human body. In some cases, however, it is necessary for a patient to avoid direct sunlight for up to 30 days to avoid sunburn or phototoxic side effects of the photoreactive agents that are infused into the body.
Teachings in the prior art have shown that it is possible, in certain cases, to obtain improved therapeutic results in PDT at a low light level. As reported by J. A. Parrish in xe2x80x9cPhotobiologic Consideration in Photoradiation Therapy,xe2x80x9d pp. 91-108, Porphyrin Photosensitization, Plenum Press, (1983), preliminary laboratory studies with hematoporphyrin and visible light suggest that the reciprocity effect does not always hold, and that low light intensity may be more effective in PDT, in an absolute sense. In these experiments, subcutaneous tumors in the flanks of newborn rats were treated with the same external dose of 620 nm radiation at intensities of 7.5, 28, and 75 mW/cm2. At the same total light dosage, Parrish found that greater tumor necrosis occurred at the lowest light intensity used.
In addition, several researchers have shown that combinations of certain photoreactive agents and low light levels exhibit very potent cytotoxicity. Some studies have shown that more than 99% of gram-positive Staphylococcus aureus and Streptococcus faecalis bacterial cultures can be killed with the application of 52 mW/cm of broad band light from a tungsten bulb for 30 minutes, if the cultures are initially dosed with 1-10 micrograms/ml of deuteroporphyrin. Continued application of light for ten to eleven hours results in a sterile condition in the culture, i.e., no bacteria remain alive.
Labrousse and Satre xe2x80x9cPhotodynamic Killing of Dictyostelium discoideum Amoebae Mediated by 4xe2x80x2,5xe2x80x2-Diiodoflurescin Isothiocyanate Dextran. A strategy for the isolation of Thermoconditional Endocytosis Mutantsxe2x80x9d, published in Photochemistry and Photobiology, 1993, vol. 67, No. 3, pp. 531-537, have demonstrated a similar photodynamic extermination of amoebae when dosed with low concentrations of 4xe2x80x25xe2x80x2-Diiodofluorescein isothiocyanate dextran and irradiated for about 30 minutes with broad band light of 8-10 mW/cm2 from a tungsten lamp. Both of these experimental results are particularly significant because the fraction of a tungsten lamp""s output energy that can be absorbed by either photoreactive agent is small, since each agent has a narrow absorbance waveband.
For all PDT light sources, the vast majority of the optical power delivered to tissue eventually degrades to heat. From a therapy perspective, it is likely that this heat load will augment the treatment due to improved chemical reaction rates at higher tissue temperatures. It is also true that cells kept above approximately 43xc2x0 C. are not viable. This effect is, in fact, used in the treatment of cancer using hyperthermia. In that situation, an attempt is made to heat the target tumor with radio frequency (RF) energy to a temperature on the order of 43xc2x0 C.-45xc2x0 C., while maintaining surrounding healthy tissue below 43xc2x0 C. Combining hyperthermia with conventional transcutaneous PDT has been shown by B. Henderson et al. to increase the efficacy of both treatments (see xe2x80x9cInteraction of Photodynamic Therapy and Hyperthermia: Tumor Response and Cell Survival after Treatment of Mice in Vivo,xe2x80x9d Cancer Research, Vol. 45, 6071 (December 1985)). Combining hyperthermia treatment with PDT delivered, for example, by an implantable probe in accordance with the present invention, will very likely augment the effects of either treatment used alone in destroying tumors.
In an attempt to solve the limitations associated with prior art PDT protocols, Chen et al. describe in U.S. Pat. Nos. 5,571,152; 5,800,478, 5,445,608 and 6,273,904 and International application WO 99/66988, which are incorporated herein by reference, intrabody implantable light sources (either LEDs or LDs), which, in the preferred embodiments, are powered by electromagnetic induction using several coil receivers in which an external (extracorporeal) RF transmitter unit induces current, or in other embodiments are operated by a thin polymer battery controlled by pressure, light, radio signal or magnetic field.
It is well known in the art of electromagnetic field transmission and receptions that the higher the frequency of an electromagnetic field is the smaller the antenna that efficiently receives such an electromagnetic field should be, and vice versa, i.e., the lower the frequency of the electromagnetic field is the larger the antenna that efficiently receives such an electromagnetic field should be.
It is also well recognized in the art that body tissues far efficiently absorb high frequency electromagnetic fields as compared to low frequency electromagnetic fields.
Thus, the implants of Chen et al. can use high frequency electromagnetic induction and maintain small antenna size provided that they are implanted close to the skin and not deep within the body. Implanting an implant as taught by Chen et al. deeper within the body calls for lower frequency electromagnetic induction and hence larger antennas, in the range of several centimeters in diameter, which prevents implantation via a minimal invasive procedure, such as catheterization or injection, and calls for a fully invasive surgery, with all its associated limitations ranging from trauma, long hospitalization, discomfort and complications, including infections.
There is thus a widely recognized need for, and it would be highly advantageous to have, a miniature implantable light source for effecting PDT, devoid of the above limitations.
According to one aspect of the present invention there is provided a miniature light source for providing light to an internal treatment site to effect a photodynamic therapy at the site, comprising: (a) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (b) an energy storage device operably coupled via an electrical circuit to the source of light; (c) a switch operably coupled to the electrical circuit and the energy storage device; and (d) an acoustic transducer coupled to the switch, the acoustic transducer being activatable upon acoustic excitation by an external acoustic energy source for closing the switch to allow current flow from the energy storage device to the source of light.
According to another aspect of the present invention there is provided a system for providing light of a desired wavelength, several discrete wavelengths or waveband to a treatment site disposed internally within a patient""s body, to effect a photodynamic therapy of the treatment site, comprising: (a) a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (ii) an energy storage device operably coupled via an electrical circuit to the source of light; (iii) a switch operably coupled to the electrical circuit and the energy storage device; and (iv) an acoustic transducer coupled to the switch, the acoustic transducer being activatable upon acoustic excitation by an external acoustic energy source for closing the switch to allow current flow from the energy storage device to the source of light; and (b) the external acoustic energy source for activating the acoustic transducer.
According to yet another aspect of the present invention there is provided a method for providing light of a desired wavelength, several discrete wavelengths or waveband to an internal treatment site to effect a photodynamic therapy, comprising: (a) providing a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (ii) an energy storage device operably coupled via an electrical circuit to the source of light; (iii) a switch operably coupled to the electrical circuit and the energy storage device; and (iv) an acoustic transducer coupled to the switch, the acoustic transducer being activatable upon acoustic excitation by an external acoustic energy source for closing the switch to allow current flow from the energy storage device to the source of light; (b) implanting the miniature light source at the internal treatment site of a subject in need thereof; and (c) activating the acoustic transducer via the external acoustic energy source, thereby providing the light of the desired wavelength, several discrete wavelengths or waveband to the internal treatment site to effect the photodynamic therapy.
According to further features in preferred embodiments of the invention described below, the switch is configured such that the switch is closed only when the acoustic transducer receives a first acoustic excitation signal followed by a second acoustic excitation signal, the first and second acoustic excitation signals being separated by a predetermined delay.
According to still further features in the described preferred embodiments the acoustic transducer is configured for receiving a first acoustic excitation signal and a second acoustic excitation signal, the switch being closed when the first acoustic excitation signal is received by the acoustic transducer, and the switch being opened when the second acoustic excitation signal is received by the acoustic transducer for discontinuing current flow from the energy storage device to the electrical circuit.
According to still further features in the described preferred embodiments the energy storage device comprises a battery.
According to still further features in the described preferred embodiments the miniature light source is designed and operable to generate light pulses.
According to still further features in the described preferred embodiments the battery is a lithium battery.
According to still further features in the described preferred embodiments the energy storage device comprises a rechargeable device, such as a rechargeable battery or a capacitor, the rechargeable device being rechargeable by a device external to the body.
According to still further features in the described preferred embodiments the acoustic transducer is configured for receiving a first acoustic excitation signal followed by a second acoustic excitation signal, the electrical circuit configured for interpreting the second acoustic excitation signal as one of a predetermined set of commands.
According to still another aspect of the present invention there is provided a miniature light source for providing light to an internal treatment site to effect a photodynamic therapy at the site, comprising (a) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (b) an acoustic transducer being operably coupled via an electrical circuit to the source of light, the acoustic transducer being powered by acoustic energy providable by an external acoustic energy source to effect current flow to the source of light.
According to a preferred embodiment of this aspect of the present invention, the miniature light source, further comprising a capacitor in said electrical circuit, the capacitor being chargeable by the acoustic transducer and dischargeable so as to effect the current flow to the source of light.
According to an additional aspect of the present invention there is provided a system for providing light of a desired wavelength, several discrete wavelengths or waveband to a treatment site disposed internally within a patient""s body, to effect a photodynamic therapy of the treatment site, comprising: (a) a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; and (ii) an acoustic transducer being operably coupled via an electrical circuit to the source of light, the acoustic transducer being powered by acoustic energy providable by an external acoustic energy source to effect current flow to the source of light; and (b) the external acoustic energy source for activating the acoustic transducer.
According to yet an additional aspect of the present invention there is provided a method for providing light of a desired wavelength, several discrete wavelengths or waveband to an internal treatment site to effect a photodynamic therapy, comprising: (a) providing a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; and (ii) an acoustic transducer being operably coupled via an electrical circuit to the source of light, the acoustic transducer being powered by acoustic energy providable by an external acoustic energy source to effect current flow to the source of light; (b) implanting the miniature light source at the internal treatment site of a subject in need thereof; and (c) powering the acoustic transducer via the external acoustic energy source, thereby providing the light of the desired wavelength, several discrete wavelengths or waveband to the internal treatment site to effect the photodynamic therapy.
According to still an additional aspect of the present invention there is provided a miniature light source for providing light to an internal treatment site to effect a photodynamic therapy at said site, comprising: (a) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (b) a rechargeable energy storage device operably coupled via an electrical circuit to said source of light; (c) an acoustic transducer coupled to said rechargeable energy storage device, said acoustic transducer being activatable upon acoustic signal by an external acoustic energy source for recharging said rechargeable energy storage device.
According to a further aspect of the present invention there is provided a system for providing light of a desired wavelength, several discrete wavelengths or waveband to a treatment site disposed internally within a patient""s body, to effect a photodynamic therapy of the treatment site, comprising: (a) a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (ii) a rechargeable energy storage device operably coupled via an electrical circuit to said source of light; (iii) an acoustic transducer coupled to said rechargeable energy storage device, said acoustic transducer being activatable upon acoustic signal by an external acoustic energy source for recharging said rechargeable energy storage device; and (b) said external acoustic energy source for recharging said rechargeable energy storage device.
According to yet a further aspect of the present invention there is provided a method for providing light of a desired wavelength, several discrete wavelengths or waveband to an internal treatment site to effect a photodynamic therapy, comprising: (a) providing a miniature light source which comprises: (i) a source of light that produces light of a desired wavelength, several discrete wavelengths or waveband when energized by an electrical current; (ii) a rechargeable energy storage device operably coupled via an electrical circuit to said source of light; (iii) an acoustic transducer coupled to said rechargeable energy storage device, said acoustic transducer being activatable upon acoustic signal by an external acoustic energy source for recharging said rechargeable energy storage device; (b) implanting said miniature light source at the internal treatment site of a subject in need thereof; and (c) recharging said rechargeable energy storage device via said acoustic transducer and said external acoustic energy source.
According to further features in preferred embodiments of the invention described below, the method further comprising administering to the subject a therapeutically effective amount of a photodynamic therapy agent.
According to still further features in the described preferred embodiments the miniature light source further comprises a rectifier that is connected to the acoustic transducer, the rectifier converting an alternating current to a direct current. In one embodiment the direct current is supplied to energize the light source. In another embodiment the direct current is used to recharge the rechargeable energy storage device.
According to still further features in the described preferred embodiments the miniature light source further comprises a biocompatible, light transmitting, acoustic energy transmitting, material that encloses the source of light and the acoustic transducer, to form a bead, the bead being thus adapted for insertion into the internal treatment site to effect the photodynamic therapy by providing light to the treatment site.
According to still further features in the described preferred embodiments the bead is generally spherical and less than 5 mm in diameter. According to still further features in the described preferred embodiments the bead is generally semi-spherical, less than 5 mm in diameter and less than 2.5 mm in height.
According to still further features in the described preferred embodiments the source of light comprises a LED.
According to still further features in the described preferred embodiments the source of light comprises a fluorescent light source.
According to still further features in the described preferred embodiments the source of light comprises an electroluminescent source.
According to still further features in the described preferred embodiments the source of light comprises a LD.
According to still further features in the described preferred embodiments the miniature light source further comprises a light diffuser disposed to diffuse the light emitted by the source of light.
According to still further features in the described preferred embodiments the light diffuser is a lens disposed to diffuse the light emitted by the source of light.
According to still further features in the described preferred embodiments the rechargeable energy storage device is selected from the group consisting of a rechargeable battery and a capacitor.
According to still further features in the described preferred embodiments, implanting the miniature light source at the internal treatment site is effected by injection or catheterization.
According to still further features in the described preferred embodiments the injecting comprises inserting a distal end of a needle that is connected to a syringe containing the miniature light source into the treatment site, and forcing the bead from the syringe into the treatment site through the needle.
According to still further features in the described preferred embodiments activating the acoustic transducer via the external acoustic energy source is effected by placing the external acoustic energy source against a body portion of a treated subject and activating the external acoustic energy source.
According to still further features in the described preferred embodiments, the method further comprising injecting a plurality of miniature light sources into the treatment site at spaced-apart locations.
According to still further features in the described preferred embodiments the acoustic transducer comprises: a cell member having a cavity; a substantially flexible piezoelectric layer attached to the cell member, the piezoelectric layer having an external surface and an internal surface, the piezoelectric layer having predetermined dimensions for enabling fluctuations at its resonance frequency upon impinging of an external acoustic wave; and
a first electrode attached to the external surface and a second electrode attached to the internal surface.
According to still further features in the described preferred embodiments the acoustic transducer comprises a transducer element adapted for converting acoustic wave energy transmitted through an external fluid medium into electric energy, the transducer element comprising: a cell member having a cavity; a substantially flexible piezoelectric layer peripherally attached to the cell member so as to isolate the cavity from the external fluid medium, the cavity containing gas and having a substantially lower acoustic impedance than the external fluid medium, a central portion of the piezoelectric layer not rigidly affixed with respect to the cavity, the piezoelectric layer having an external surface and an internal surface, the piezoelectric layer featuring such dimensions so as to enable fluctuations thereof in-and-out of the cavity at its resonance frequency upon impinging of an acoustic signal transmitted through the external fluid medium, the resonance frequency determined by the physical dimensions of the cavity and the piezoelectric layer wherein the wavelength of the acoustic signal is substantially larger than the dimensions; and a first electrode attached to the external surface and a second electrode attached to the internal surface.
According to still further features in the described preferred embodiments the cavity is etched or drilled into a substrate.
According to still further features in the described preferred embodiments the substrate includes an electrically insulating layer and an electrically conducting layer.
According to still further features in the described preferred embodiments the first electrode is integrally made with a substantially thin electrically conducting layer disposed on the substrate.
According to still further features in the described preferred embodiments the substantially thin electrically conducting layer is connected to the substrate by means of a sealing connection.
According to still further features in the described preferred embodiments the electrically insulating layer is made of silicon.
According to still further features in the described preferred embodiments the electrically insulating layer is made of a polymeric material.
According to still further features in the described preferred embodiments the piezoelectric layer is made of PVDF.
According to still further features in the described preferred embodiments the cavity is circular in cross section.
According to still further features in the described preferred embodiments the cavity is elliptical in cross section.
According to still further features in the described preferred embodiments the cavity is hexagonal in cross section.
According to still further features in the described preferred embodiments the substrate includes a plurality of cell members.
According to still further features in the described preferred embodiments at least one of the first and second electrodes is specifically shaped so as to provide a maximal electrical output.
According to still further features in the described preferred embodiments at least one of the electrodes features first and second electrode portions interconnected by a connecting member.
According to still further features in the described preferred embodiments the gas is of substantially low pressure.
According to still further features in the described preferred embodiments the miniature light source is preprogrammed to shut off a predetermined time period following its activation.
According to still further features in the described preferred embodiments the miniature light source shuts off following a reception of an external shut off signal.
The present invention successfully addresses the shortcomings of the presently known configurations by providing an intrabody implantable light sources which, are powered and/or controlled by acoustic energy or signals, respectively, and hence, can be miniature and, at the same time, be implanted deep within the body.
Implementation of the device, method and system of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of preferred embodiments of the device, method and system of the present invention, several selected steps could be implemented by hardware or by software on any operating system. For example, as hardware, selected steps of the invention could be implemented as a chip or a circuit. As software, selected steps of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In any case, selected steps of the device, method and system of the invention could be described as being performed by a data processor, such as a computing platform for executing a plurality of instructions.